Obstructive sleep apnea and vitamin D level: Has the dust settled?

Abstract Obstructive sleep apnea and vitamin D deficiency are associated with multiple complications with increased morbidity and mortality. However, the relationship between these two entities remains unclear, with clinical studies demonstrating contradictory results. This narrative review aims to present the current evidence and understanding of this relationship and discuss the possible mechanisms linking these two disease entities. Finally, we summarize and propose areas of opportunity for future research.


| INTRODUCTION
Obstructive sleep apnea (OSA) is a chronic disease, characterized by recurrent partial or complete upper airway collapse during sleep leading to intermittent hypoxia and sleep disruption. 1,2Abrupt oxygen desaturation during sleep leads to brief arousal from sleep in order to terminate the obstruction and restore normal breathing. 3This causes substantial sleep fragmentation and impaired sleep quality.The prevalence of OSA has been increasing over the years, especially in developed countries. 4,5OSA is commonly found in patients with obesity.This is believed to be due to fat deposits in the upper airway with reduction of muscle activity in that region leading to hypopneic and apneic episodes. 6SA has been demonstrated as an independent risk factor for cardiovascular diseases and is associated with increased cardiovascular morbidity and mortality. 7,80][11] A recent meta-analysis demonstrated that patients with OSA have higher level of renin-angiotensinaldosterone system hormones, blood pressure, and heart rate compared with those without OSA, which may add on to the increased cardiovascular risks among this cohort. 12lthough traditionally, vitamin D is thought to play its main role in calcium homeostasis and regulation, there is now increasing evidence that low vitamin D level is associated with a multitude of cardio-metabolic complications, which has sparked new interests in these extra-skeletal associations. 13][16][17] Vitamin D levels are associated with respiratory function. 18OSA and vitamin D deficiency seem to share common risk factors, such as obesity and increasing age.These two conditions have almost similar pathogenesis, such as involvement of inflammatory reactions and oxidative stress, although the exact mechanism is poorly understood.To date, studies examining the relationship between these two entities have shown contradictory results.The association is likely to be bi-directional, multi-factorial, and complex.To better comprehend the relationship between these two entities, this review aims to summarize the current evidence and to present the possible mechanisms and understanding of this association.

| CLINICAL STUDIES OF OSA AND VITAMIN D 2.1 | Vitamin D level in OSA
Among 139 patients with OSA, vitamin D level was significantly lower compared with 30 non-apneic cohort (17.78 ± 7.8 vs. 23.9 ± 12.4 ng/mL, p = 0.019).However, those with OSA were older and had significantly higher body mass index (BMI), neck, waist, and hip circumferences, which could have contributed to the lower level of vitamin D. 19 Nevertheless, even among BMI-matched obese male patients, vitamin D level was still significantly lower among those with OSA compared with those without, 20,21 suggesting a relationship between OSA and vitamin D deficiency irrespective of weight.In addition, vitamin D level was noted to have inverse correlation with sleep stage transitions, which are indicators of sleep continuity. 19Furthermore, the level was demonstrated to be inversely correlated with disease severity even after multi-variate analysis, 20,[22][23][24][25][26][27] suggesting the role of sleep fragmentation in vitamin D deficiency.This may be the reason why lower level of vitamin D is more pronounced in severe OSA compared with those without OSA. 23,24imilarly, the number of patients with vitamin D deficiency was reported to be higher in the OSA group compared with those without OSA. 24,25Although few studies found no significant difference in vitamin D level between these two cohorts, these studies still demonstrated that the number of patients with vitamin D deficiency, especially at a level of <10 mcg/dL, was higher in the OSA group, and more pronounced with increasing disease severity, compared with those without OSA. 22,28,29

| Vitamin D level in elderly
The difference in vitamin D level was not apparent among the elderly cohort.Among 72 hospitalized geriatric patients with mild dementia and confirmed OSA, vitamin D level was not significantly different compared with those without OSA (p = 0.082). 30This could be due to less severe OSA encountered in this study.Nevertheless, the level of vitamin D was demonstrated to reduce with increasing OSA severity (mild OSA 13.5 ng/mL [8.7,  31.2];moderate OSA 7.9 ng/mL [5.3, 22.6]).
Similarly, in a community-dwelling elderly cohort with a wide range of BMI, there was no significant difference in the prevalence of vitamin D deficiency.Besides, no association was demonstrated between vitamin D level and apnea hypopnea index (AHI). 31Nevertheless, those with lowest quartile of vitamin D concentrations had higher odds of severe sleep apnea.Sensitivity analysis suggested that this association was largely explained by greater BMI and larger neck circumference among men with hypovitaminosis D. 32

| Vitamin D level in metabolic syndrome
Among patients with type 2 diabetes, there was no demonstrated significant difference in vitamin D level between those with OSA and those without (p = 0.086). 33owever, OSA patients with metabolic syndrome had higher prevalence of vitamin D deficiency, which is most pronounced among those with severe metabolic syndrome (metabolic index >3). 34They also had significantly lower vitamin D level compared with those without metabolic syndrome (18 ± 8.6 vs. 23.9 ± 14.1 ng/mL, p = 0.012). 35Low vitamin D level was noted to be associated with increased abdominal obesity, elevated triglyceride level, and reduced HDL-cholesterol level, as well as diabetes mellitus in this cohort of patients. 36

| Clinical characteristics
OSA patients with vitamin D deficiency were more likely to be females, older, African Americans, with higher BMI, and larger waist circumference compared with those who were vitamin D sufficient. 25,36These individuals had concurrent metabolic syndrome and diabetes mellitus.There was no correlation found between vitamin D level and excessive daytime sleepiness. 22,37The threshold AHI for vitamin D deficiency was reported to be 19.3 (sensitivity 55.8%, specificity 71.8%), 24 suggesting that vitamin D deficiency is more pronounced among those with moderate to severe OSA, and the level worsens with OSA severity.
The articles reviewed are summarized in Table 1.

| Outcome of continuous positive airway pressure (CPAP) treatment on vitamin D level
Although treatment with CPAP among patients with moderate to severe OSA for 12 weeks did not significantly alter vitamin D level, some changes were seen at 24 weeks among those with severe OSA and with excessive sleepiness. 38This suggests that CPAP may have late beneficial effect and exerts more benefit on vitamin D level particularly among those with severe OSA.Nevertheless, the median vitamin D level of this cohort falls within the sufficient range of 50.9 ng/mL, which may explain the non-significant difference seen with CPAP treatment.Further improvement of vitamin D level was demonstrated among male OSA patients who initially responded well to a year of adequate CPAP therapy usage. 39These findings were consistent with another study that demonstrated that vitamin D levels were positively correlated with higher daily CPAP usage, especially among those who were adherent to CPAP therapy. 40,41This suggests that improving hypoxia by normalizing nocturnal oxygen saturation may positively affect vitamin D level.
The studies examining effect of CPAP treatment on vitamin D level among patients with OSA are summarized in Table 2.

| Outcome of vitamin D supplementation on OSA severity
The data of vitamin D supplementation use in patients with OSA are limited.There are only two studies identified, and both were limited by small sample sizes.Among 19 male patients with mild OSA who were not on CPAP, the use of vitamin D3 at 50 000 IU a week for total of 8 weeks significantly reduced OSA severity in terms of oxygen desaturation index, AHI, hypopnea index, and the number of OSA patients. 42The second study evaluated the use of vitamin D3 at 4000 IU per day (n = 10) versus placebo (n = 9) for 15 weeks among patients with OSA of different severity categories and heterogenous CPAP usage.Significant improvement in LDL and lipoprotein-associated phospholipase A2 was observed; however, post-intervention OSA severity was not assessed. 43In this respect, more robust studies are needed to study the effect of adequate vitamin D supplementation in patients with OSA.

| Sleep duration and sun exposure
Sun exposure is essential in initiation of cutaneous vitamin D synthesis.However, patients with OSA experience nocturnal hypoxia and sleep fragmentation, which may lead to daytime drowsiness and fatigue.This may cause reduction in outdoor activities, leading to lack of sun exposure with subsequent reduction in vitamin D synthesis. 44Indoor workers are consistently reported to experience vitamin D insufficiency or deficiency, suggesting the lack of exposure to ultraviolet light leading to reduction in vitamin D level. 45In addition, short sleep duration of less than 6 h a night secondary to sleep fragmentation was reported to be associated with lower level of vitamin D. These individuals have twice increased odds of having vitamin D deficiency, independent of age, gender, seasonality, BMI, and ethnicity. 46,47n the other hand, vitamin D deficiency, especially at a level of <20 ng/mL (<50 nmol/L), was shown to be associated with increased risk of sleep disorders, including poor sleep quality, shorter sleep duration, and sleepiness, 48 which could contribute to worsening of OSA.The use of vitamin D supplementation among patients with sleep disorders led to significant improvement of sleep quality, reduction of sleep latency, and increment of sleep duration. 49,50This further strengthens the relationship between vitamin D deficiency and sleep disorders.
2][53][54] The decline of vitamin D level in the aging process is associated with reduction in skin production of vitamin D, decreased vitamin D receptor (VDR), and reduced ability of renal production of active vitamin D. 55 This may explain the non-significant difference seen between those with OSA and those without among the elderly.

| Hypoxia
The association between vitamin D deficiency and OSA is also believed to be related to hypoxia involving hypoxia-inducible factor 1-α (HIF1-α). 40HIF1-α is the main factor for oxygen metabolism homeostasis, and its expression is shown to increase in OSA. 56The use of vitamin D3 reduced protein expression, transcriptional activity, and target genes of HIF1-α in various human cancer cells, 57 substantiating the relationship between vitamin D deficiency and hypoxia.[40][41]

| Obesity
A high proportion of patients with OSA are overweight or obese.Observational studies have demonstrated the relationship between low vitamin D level and obesity to be bi-directional. 58Vitamin D deficiency increases risk of obesity, whereas obesity lowers vitamin D level.Being fat-soluble, vitamin D is predominantly stored in adipose tissue.Moreover, VDR and the enzymes involved in producing the active form of vitamin D are also expressed in these adipose tissues. 40Vitamin D is thus believed to be trapped in the adipose tissue, leading to reduced bioavailability and hence low level of vitamin D in the blood. 59is is also contributed by an increased catabolism of vitamin D by local action of 24-hydroxylase enzyme found in human adipose tissue. 27In contrast, some believe that volumetric dilution of vitamin D, instead of sequestration, in the large adipose stores was the reason leading to low serum vitamin D level. 60Nevertheless, both theories suggest that obesity plays an important role in vitamin D deficiency in patients with OSA.This is worsened by chronically raised abdominal pressure seen in those who are obese, which may also lead to gastro-esophageal reflux and gastric ischemia, thereby affecting vitamin D absorption causing vitamin D deficiency. 27,61eptin is a type of adipokine that is a proinflammatory factor predominantly formed by adipose cells.Increment of adipose tissue volume seen in obesity leads to adipocyte hypertrophy, which subsequently causes increment of leptin production. 62High levels of leptin were shown to impair vitamin D metabolism by attenuating gene expression responsible for the activation of vitamin D. 63 On the other hand, the active form of vitamin D modulates adipogenesis and regulates adipocyte differentiation by binding to the nuclear VDR with high affinity. 64ence, a low vitamin D level causes adipose tissue dysregulation leading to obesity and thus increases the risk of OSA. 65The use of active vitamin D in both animal and human tissues inhibited adipocyte differentiation, 64 depicting the role for low vitamin D status in development of obesity.LOH and SUKOR

| Metabolic syndrome
Vitamin D level is inversely associated with the presence of metabolic syndrome. 66,67Low vitamin D status could magnify the adverse effects of obesity on the metabolic variables, including insulin resistance and hypertension. 36,68Vitamin D-deficient rats exhibited close to 50% reduction in insulin secretion compared with those which were replenished with activated vitamin D. 69 Pancreatic β cells express VDR, and the activated form of vitamin D is shown to stimulate insulin secretion. 702][73] This may explain why there is no difference seen in vitamin D level between diabetic patients with and without OSA, as vitamin D deficiency is commonly seen in patients with type 2 diabetes regardless of age, gender, and insulin treatment. 33esides, vitamin D and VDR are demonstrated to be directly involved in the modulation and inflammatory pathways leading to the development of metabolicassociated fatty liver disease (MAFLD), especially among the overweight and obese cohort. 74This occurs via liver homeostasis, intra-hepatic regulation of insulin sensitivity, fat accumulation, and gut homeostasis. 74On the other hand, liver disease also impairs protein synthesis and reduces production of vitamin D binding protein (VDBP), leading to a decreased total vitamin D level. 75As patients with OSA and metabolic syndrome are at higher risk of MAFLD, the reduction of vitamin D synthesis and VDBP could contribute to development of vitamin D deficiency. 76,77he development of chronic kidney disease from the presence of concurrent diabetes and hypertension may also influence vitamin D status and function. 78With deteriorating kidney function, there is a slow progressive decline in active vitamin D level due to reduction in renal mass, decreased glomerular filtration rate, and effect of fibroblast growth factor-23 on the synthesis of active vitamin D. 79 The transport capacity for VDBP from the glomerular filtrate into the renal tubules is similarly reduced in chronic kidney disease. 75

| Autonomic dysfunction
In healthy individuals, sympathetic neural activity decreases with a concurrent rise in parasympathetic activity during sleep. 80However, in patients with OSA, upper airway obstruction and hypopnea are postulated to cause autonomic dysfunction, 81 with abnormal parasympathetic activity persisting beyond sleep. 82As vagal nervous system plays a major role in gastrointestinal motility, abnormal parasympathetic activity in patients with OSA is believed to cause reduction in gastrointestinal motility and gastrointestinal hormone secretion leading to reduced vitamin D absorption. 44,832 | Vitamin D deficiency worsening OSA

| VDR gene polymorphism
VDRs are widely distributed throughout many tissues, including the brain regions, which are involved in sleep regulation. 84,85Patients with OSA were found to have higher frequency of VDR FokI CC genotype, which was associated with lower vitamin D level, compared with non-OSA controls. 86In logistic regression analysis, the interaction of vitamin D with VDR FokI polymorphism was associated with higher risk of OSA occurrence after adjustment for various risk factors. 86Furthermore, VDR FokI polymorphism could affect severity of OSA symptoms.A higher frequency of VDR FokI CC genotype was found in OSA patients with excessive daytime sleepiness. 86Nevertheless, VDR activity may be confounded by ethnic variation. 86,879][90][91] The underlying mechanism of this difference remains unclear.

| Vitamin D and skeletal muscle
Vitamin D plays a role in active calcium transportation into muscle via Ca-ATPase, as well as regulating muscular contractions. 92Muscle weakness is one of the prominent features of vitamin D insufficiency.Chronically low vitamin D level may cause non-inflammatory myopathy of upper airway muscle due to impaired cellular calcium transportation into the sarcoplasmic reticulum and mitochondria. 84This leads to reduced pharyngeal patency and predisposes patients to apneic events during sleep. 93esides, vitamin D deficiency is reported to increase the risk of nasal airflow restriction, 84 hence further worsening sleep apnea.

| Inflammatory cytokines
Chronic variations in vitamin D levels also affect humoral mechanisms as vitamin D harbors immuno-modulatory properties. 94A deficient in this vitamin causes immune dysregulation leading to a rise in inflammatory cytokines, including TNF-α, which is shown to affect sleep architecture by enhancing slow-wave sleep. 84,95In healthy women, this cytokine was demonstrated to be inversely related to serum vitamin D level. 96nterleukin-17 (IL-17), a pro-inflammatory cytokine, was also found to be significantly elevated in patients with severe OSA compared with non-OSA controls. 97A negative correlation was demonstrated between IL-17 and vitamin D level among those with severe OSA. 97Additionally, people who have inadequate vitamin D are found to have increased risk of infection and inflammation of upper and lower airway. 84This can cause adenotonsillar hypertrophy, which can worsen airway obstruction in patients with OSA.
The proposed mechanisms of the bidirectional relationship are summarized in Figure 1.

| RESEARCH GAPS AND FUTURE DIRECTION
Despite the comprehensive summary of the clinical studies and possible mechanisms linking OSA and vitamin D deficiency, there remains gaps in the current literature in this area.Both of these increasingly common diseases are closely related to increased cardio-metabolic risks with increased morbidity and mortality. 98,99It remains unclear whether vitamin D deficiency is a risk factor for OSA or whether OSA is a risk factor for vitamin D deficiency, and the role of other confounding factors in these two disease entities.As clear relationship between OSA and vitamin D deficiency is yet to be established, larger prospective studies to examine the link between the two are needed.This is necessary to better understand the relationship, mechanism of vitamin D deficiency in patients with OSA, and the correlation between vitamin D levels and severity of OSA.
The effect of VDR and VDBP gene polymorphism in OSA remains unclear.Hence, research is needed to examine the role of VDR and VDBP genetic variants and possibly their mutations in OSA severity and OSA-related metabolic disorders.Inter-ethnic variations in this genetic polymorphism and mutations are also needed to understand the difference observed in the FokI genotype in different ethnic groups.
Other plausible mechanisms that warrant more robust future research include inflammatory pathways involved, associations with adipokines, and the role of autonomic dysfunction linking OSA and vitamin D deficiency.
Furthermore, the use of vitamin D supplement in the OSA cohort is very limited.Hence, prospective studies F I G U R E 1 Relationship between obstructive sleep apnea and vitamin D deficiency.CKD, chronic k; HIF1-α, hypoxia-inducible factor 1-alpha; MAFLD, metabolic-associated fatty liver disease; OSA, obstructive sleep apnea; VDR, vitamin D receptor.
with bigger sample sizes are essential to determine the effect of vitamin D, as well as the dose and duration needed to bring benefits to patients with OSA.There is a lack of evidence in the role of vitamin D in improving OSA severity; whether vitamin D supplementation would alter the course of OSA, as well as its related metabolic disturbances, such as diabetes mellitus, hypertension, and dyslipidemia remains unanswered.Although current evidence suggests beneficial effects of CPAP therapy on vitamin D levels in patients with OSA, long-term studies are lacking to better understand the benefits of CPAP on cardiovascular morbidity and mortality outcomes beyond improvement of vitamin D levels in these patients.

| CONCLUSION
The present review aimed to collect and put into perspective current available literature regarding the association between OSA and vitamin D level.It focused on the potential relationship between these two entities and presented evidence for potential causal links and underlying mechanisms.Current evidence suggests a relationship between OSA and low levels of vitamin D via inflammatory and non-inflammatory pathways, genetic polymorphisms of VDR and VDBP, and autonomic nervous system.The coexistence of obesity and hence increased adipose tissue contributes to the sequestration and catabolism of vitamin D and impaired adipokine function.Hypoxia secondary to sleep fragmentation leading to reduced outdoor activities and sun exposure may play a role linking these two disease entities as well.The presence of liver and kidney disease associated with metabolic disorders seen in these patients can lead to lower vitamin D level.Nevertheless, further robust prospective studies with larger sample sizes are needed to examine this link and the long-term beneficial effect of OSAdirected therapy in increasing vitamin D level.It is essential to determine the role of vitamin D supplementation in improving OSA severity and altering the course of OSA.Because untreated OSA and vitamin D deficiency independently lead to increased cardiovascular morbidity and mortality, early recognition through effective screening and diagnosis and a timely targeted treatment are necessary to reduce the risk of adverse sequelae related to OSA and vitamin D deficiency.
Summary of papers reviewed.
T A B L E 2 Effect of CPAP on 25OHD level among OSA.